The overall goal of this project is to identify patterns of brain function that contribute to or result from dependence on drugs, and to suggest leads in the development of new treatment methods. Our research strategy is use positron emission tomography (PET) to evaluate the effect of various drugs of abuse and cognitive activation on cerebral metabolic rates for glucose metabolism using [F-18]fluorodeoxyglucose as the radiotracer and cerebral blood flow using [O-15]-water as the radiotracer. Both of these methodologies provide indices of human brain function. The research includes assessments of cognitive and neuropsychological performance during the imaging sessions. The relationship between cocaine craving and cerebral glucose metabolism in cocaine abusers was examined. Cocaine cues elicited a higher degree of craving than previously reported and resulted in left hemispheric activation of lateral amygdala, lateral orbitofrontal cortex and rhinal cortex, and right hemispheric activation of dorsolateral prefrontal cortex and cerebellum. The intensity of activation in these areas (except cerebellum), as well as left insula, was also correlated with craving. Deactivation occurred in left ventral pole and left medial prefrontal cortex. The results suggest that induction of drug craving involves a neural network that assigns incentive motivational value to environmental stimuli through the co-activation of brain regions that process information about memories and emotions. The effect of nicotine on cerebral blood flow and memory in smokers and ex-smokers was examined. Abstinent smokers, but not ex-smokers showed significantly improved performance on the memory test after given nicotine gum, compared with their performance after placebo gum. The decreased blood flow in some regions of the smokers' brains compared with increased cerebral blood flow in ex-smokers after chewing nicotine gum is the first evidence of tolerance to nicotine measured directly in the human brain. The effects of the benzodiazepine, triazolam (Halcion), on memory performance and cerebral blood flow revealed an association between decreased blood flow in the anterior cingulate cortex, the cerebellum and the precuneous and impaired performance on the memory task compared to the placebo condition. In PET blood flow studies of 20 control subjects, we observed activation of the anterior cingulate, orbital frontal, dorsolateral prefrontal and inferior parietal cortices, insula and thalamus predominantly on the right side during decision-making (Iowa gambling task). This task also activated the cerebellum predominantly on the left side. Studies of individuals with histories of cocaine abuse, who were abstinent for 25 days, compared to a matched control group demonstrated differential effects on blood flow while the participants performed tasks of sustained attention (Stroop Color Word Interference task) and decision-making (Iowa gambling task). While performing the Stroop task, abusers have less activation in the left anterior cingulate cortex and right dorsolateral prefrontal cortex than control subjects. Whereas, compared to control subjects performing the Gambling task, cocaine abusers have greater activation in the right orbital frontal cortex and less activation in the dorsolateral prefrontal cortex bilaterally. Grams per week of cocaine used prior to the 25-days abstinence period correlates negatively with normalized blood flow in the predicted regions of interest for both tasks. In another PET blood flow study, preliminary results indicate reduced normalized blood flow in the orbitofrontal cortex, hippocampus, and amygdala in abstinent drug abusers relative to control subjects during performance of executive and emotional function tasks. In addition, physiological responses measured by skin conductance and heart rate are altered in substance abusers during tests of executive function. These results suggest that both cognitive impairment and reduced blood flow characterize drug abusers, and that these differences persist after a minimum of three months of abstinence. PET studies of glucose utilization during a continuous performance task in individuals with a history of opiate abuse showed that detoxified opiate abusers previously on methadone maintenance therapy have lower normalized glucose metabolism in the left midcingulate gyrus, the left superior frontal cortex and the insula, bilaterally compared to individuals who have had no history of drug abuse. Methadone maintained opiate abusers also have lower metabolism in the left insula, but higher metabolism in the left inferior parietal cortex. These results suggest that opiate addiction leads to abnormalities in neural circuitry subserving negative affective states and the methadone maintenance alleviates these abnormalities. Under the guidance of the new Branch Chief, Elliot Stein, who officially joined NIDA IRP in late February 2002, the branch added a new fMRI Section. After evaluating various MRI scanners, the branch designed and built a scanner suite and purchased a Siemens Allegra 3Tesla machine, which arrived in late August and is currently operational. Research involving several new, IRB-approved human protocols will begin shortly. New staff have been hired including 2 Staff Clinicians, an MRI physicist (Investigator), a signal processing physicist (Staff Scientist), an MRI operator, 2 IRTA postdoctoral fellows and a research technologist.